L evofloxacin,
the active l -isomer of ofloxacin, has all of the excellent
features of its parent compound, and the additional advantages
of being even more effective against a wider spectrum of bacteria
at half the dosage, making it exceedingly well tolerated. These
characteristics have rapidly proven levofloxacin to be one of
the most promising of the new fluoroquinolones. Levofloxacin's
broad spectrum of activity encompasses most of the common pathogens
of the respiratory tract, and its pharmacokinetic features allow
it to penetrate extremely well into lung tissue and bronchial
secretions. Such attributes have earned levofloxacin the title
of a "respiratory" quinolone, and its efficacy in a once-daily
dosing schedule and good safety profile, have made it well accepted
by most patients.

To characterise the role of levofloxacin in the treatment
of acute bacterial exacerbations of chronic bronchitis (ABECB),
one of the respiratory tracts most ubiquitous infections,
Penetration interviewed Dr. Carl A. DeAbate, Medical Director,
Medical Research Center, New Orleans, USA. He has recently performed
a clinical study comparing levofloxacin versus cefuroxime axetil
in the treatment of adult outpatients with ABECB. Dr. DeAbate
was able to draw on his wide experience in treating respiratory
tract infections (RTI) to discuss the role of levofloxacin in
the therapy of these common infections.

Q1. Could you
comment on the pharmacokinetic features of levofloxacin that
make it a useful drug in acute bacterial exacerbations of chronic
bronchitis (ABECB)?

A1. Levofloxacin possesses the excellent pharmacokinetic
properties of ofloxacin, its parent compound. In addition, it
has two to four times the potency of ofloxacin in vitro
, and demonstrates exceptional activity against most aerobic
Gram-positive and Gram-negative organisms associated with respiratory
tract infections (RTI). There are several other properties of
levofloxacin that contribute to its usefulness. It is rapidly
absorbed, is extensively distributed into the tissues, and concentrations
of the drug are typically found to be higher in the tissues
or body fluids than in plasma. Peak plasma concentrations are
seen in less than two hours and are dose-dependent
(1) . With approximately 90% of the dose excreted in the
urine, a half-life of six to seven hours, and a post-antibiotic
effect of two to three hours, levofloxacin can be used as a
very effective once-daily therapy, which offers convenience
and increased compliance for ABECB patients.

Q2. What advantages
does this pharmacokinetic profile give levofloxacin over other
fluoroquinolones?

A2. Several issues come to mind when we compare levofloxacin
to other fluoroquinolones, and perhaps the most important is
the problem we have encountered with resistance. Levofloxacin
has two important advantages over many other fluoroquinolones
in this regard. Firstly, it uses two mechanisms of action for
bactericidal activity, one requiring RNA and protein synthesis,
and another which does not. Most of the other fluoroquinolones
use only one method, so the risk of developing resistance to
them is higher. The second advantage with levofloxacin is its
use as a single once-daily dose, which significantly reduces
the risk of developing resistance compared with other fluoroquinolones
which must be taken more frequently. Of course, the fact that
it demonstrates 100% bioavailability, has a broad spectrum of
activity, and produces comparatively fewer side effects also
contribute to its favorability over other fluoroquinolones.

Q3. What pharmacodynamic
advantages does levofloxacin provide in the treatment of ABECB?

A3. The observation that levofloxacin penetrates
well into bronchiolar tissue and sputum is significant when
treating patients with RTI. The sputum concentration of the
drug following oral administration has been reported to range
from approximately 85% to 95% of serum concentrations
(2) . These findings suggest that clinically effective concentrations
of levofloxacin are achieved at target respiratory sites, exceeding
the minimum inhibitory concentrations (MIC) for common respiratory
pathogens. It also exhibits greater activity against streptococci
than both ciprofloxacin and ofloxacin and a greater potency
against many anaerobes and Gram-positive organisms.

Q4. What are the
usual pathogens involved in ABECB and how does this relate to
the antibacterial spectrum of levofloxacin? How do the MIC values
compare to other available treatments?

A4. Typical pathogens in ABECB include organisms
such as Staphylococcus aureus, Streptococcus pneumoniae,
Haemophilus influenzae, Haemophilus parainfluenzae,
and Moraxella catarrhalis, all of which are susceptible
to levofloxacin. Previous studies have shown that the MIC90
values are approximately 50% lower against Gram-positive and
Gram-negative organisms than ofloxacin and three to four times
lower than ciprofloxacin for methicillin-resistant S. aureus
(MRSA) and methicillin-susceptible S. aureus (MSSA)
(3) .

Q5. What is the
role of atypical pathogens in ABECB and how effective is levofloxacin
compared to other commonly used agents against these bacteria?

A5. Atypical pathogens such as Mycoplasma pneumoniae,
Chlamydia pneumoniae, and Legionella pneumophila
are important to identify as disease-causing agents because
they can contribute to superinfections, so a drug that can eradicate
both the typical and atypical pathogens at the same time is
desirable. Levofloxacin has shown excellent activity against
these organisms and is as effective as other standard therapies.
With resistance to traditional therapies becoming such as issue,
it is important that we can identify a medication such as levofloxacin
which offers both potency and safety with a shorter dosing time.

Q6. Could you
comment on any other studies comparing levofloxacin to other
antimicrobials (for example cefaclor) in the treatment of ABECB?

A6. Results from a recent trial comparing oral levofloxacin
500 mg daily to cefaclor 250 mg three times daily in patients
with ABECB found that among clinically evaluable patients treated
with levofloxacin, 72.1% were cured and 19.5% improved compared
with 64.5% cured and 27.1% improved with cefaclor. The microbiologic
eradication rates by pathogen were 95% for levofloxacin and
86.5% for cefaclor. There was 100% eradication of H. influenzae,
94.7% eradication of M. catarrhalis, and 90% eradication
of S. pneumoniae for levofloxacin, compared to eradication
rates of 70.8%, 100% and 85.7%, respectively, for the cefaclor
group. The findings indicate that levofloxacin given for five
to seven days was as effective as cefaclor given for seven to
ten days for ABECB (4) . Interestingly
the results of this study were similar to results obtained from
our study comparing levofloxacin and cefuroxime axetil.

Q7. With the oral
form of levofloxacin possessing excellent pharmacodynamic properties
could it be used in place of alternative intravenous forms of
therapy?

A7. Oral therapy with levofloxacin could replace
intravenous (IV) therapy in most cases, unless the patient is
incapacitated in some way in which it would be more practical
to use an IV method. Peak plasma concentrations (Cmax)
are very similar and the oral form is both less expensive and
easier to administer than IV therapy.

Q8. Would you
use levofloxacin in combination with other antibiotics in ABECB?

A8. I think combination therapy with levofloxacin
could be very advantageous in the treatment of immunocompromised
or elderly patients, particularly where resistance is an issue.
We see resistance to staphylococci everyday, and the use of
both levofloxacin and rifampin would likely be an effective
method of treatment. The key is to use a combination of drugs
which act in time-dependent and concentration-dependent killing
manners, such as a ß-lactam with levofloxacin. In this
scenario, we achieve a wide range of activity by utilising the
different killing mechanisms of both classes, which provides
us with greater potential for treatment and cure.

Q9. You have performed
a comparative study to evaluate levofloxacin in the treatment
of ABECB? Could you discuss this?

A9. Our study was designed to compare the clinical
efficacy and tolerability of levofloxacin with cefuroxime axetil
in the treatment of adult outpatients with ABECB. Cefuroxime
axetil is a widely used broad-spectrum ß-lactam antibiotic
often selected as primary empiric therapy for these infections
because of its broad spectrum of activity. The study was an
open-label trial in which patients who met entry criteria were
randomly assigned to receive either one 500 mg tablet of levofloxacin
orally once-daily for five to seven days or one 250 mg tablet
of cefuroxime axetil orally twice-daily for ten days. The patients
were adults who were experiencing an episode of ABECB and who
could receive oral medication. The diagnosis of ABECB was based
on a history of chronic obstructive pulmonary disease (COPD),
including chronic bronchitis and emphysema; a recent increase
in cough; a change in the quality of sputum; and physical findings
consistent with ABECB. Patients who had received prior antibiotic
therapy could be enrolled if the therapy had lasted less than
24 hours or if there had been no stabilisation or improvement
by prior therapy. Patients with acute bronchitis, pneumonia,
cystic fibrosis or any other disease interfering with evaluation
of either study drug were excluded. A thoracic radiograph was
performed and Gram stain and culture were performed on sputum
collected within 48 hours before admission. Respiratory specimens
also included deep expectorated or suctioned sputum, transtracheal
aspirates, or bronchial brushings, biopsies, or washings. Patients
returned for a scheduled visit and evaluation of clinical progress
on days three to five of study drug administration. Those patients
with negative culture results on admission were allowed to continue
in the study. Those with pathogens resistant to the study drug
were allowed to remain in the study if there had been reasonable
clinical improvement during the study. A post-therapy visit
was scheduled for five to seven days after termination of therapy
at which time a physical examination and repeat laboratory testing
were performed.

A10. We assessed efficacy based on clinical signs
and symptoms, clinical response rates, and microbiological eradication
rates. Clinical symptoms of ABECB included chills, chest pain,
shortness of breath, increased cough, increased sputum, and
purulent sputum, which were graded as present or absent. Clinical
signs included diminished breath sounds, rales, egophony, rhonchi,
and wheezes. These were graded as none, mild, moderate or severe.
At the post-therapy visit the clinical response was evaluated
as cured, improved, failed or unable to evaluate. A clinical
cure was defined as a resolution of the signs and symptoms;
a clinical improvement was defined as an incomplete resolution
of signs or symptoms with no further need for antimicrobial
therapy; and a lack of response to therapy was deemed a clinical
failure. If the patient could produce sputum, Gram stain, culture
and sensitivity testing were carried out to assess microbiological
response, which was assessed as eradicated, persisting or unknown.
Susceptibility testing was performed for levofloxacin and cefuroxime
axetil on pathogens isolated at admission and at the post-therapy
visit if possible. For safety evaluations, we assessed the incidence
of treatment-emergent adverse events; results of laboratory
testing; and physical examination findings including vital sign
measurements.

Q11. Could you
describe the clinical results of your trial investigating levofloxacin
in ABECB?

A11. This study was conducted at 34 centres and included
492 patients, of whom 248 received levofloxacin and 244 received
cefuroxime axetil. The demographic characteristics and disposition
of patients in the two study groups are outlined in
Tables 1, 2 (5) . The clinical
response was rated a success, with the patient cured or improved
in 94.6% of those receiving levofloxacin and 92.6% of the cefuroxime
axetil group
(Table 3, Figure 1) (5) . All
of the symptoms of bronchitis were resolved in more than 86%
of the patients, with the exception of shortness of breath,
which resolved in 69.7% of levofloxacin-treated and 72.4% of
cefuroxime axetil-treated patients. Resolution or improvement
of abnormalities on thoracic auscultation were noted in 85%
or more of patients, with the exception of diminished breath
sounds, which were resolved or improved in 62.5% of levofloxacin-treated
and 55.2% of cefuroxime axetil-treated patients.

Q12. How did
the microbiological response compare between levofloxacin and
cefuroxime axetil?

A12. Microbiological eradication rates for levofloxacin
were impressive overall
(Table 4) (5) . We found that
the response rates were similar, but levofloxacin had a higher
success rate overall. The microbiologic eradication rates by
pathogen were 97.4% in the levofloxacin-treated group and 94.6%
in the cefuroxime axetil-treated group, while the eradication
rates by patient were 96.3% and 93.2%, respectively. We observed
nearly twice as much microbiologic persistence in the cefuroxime
axetil treated patients (6.8%) as with the levofloxacin-treated
patients (3.7%). The drugs were comparable for both clinical
and microbiologic response, although levofloxacin had the advantage
of requiring fewer dosing days. Patients on levofloxacin required
an average of seven dosing days, while the cefuroxime axetil-treated
group was treated for ten days. This indicates that a significant
clinical response can occur with a shorter treatment regimen
of levofloxacin than cefuroxime axetil.

Q13. Could you
comment on the safety profile of levofloxacin compared to other
agents?

A13. In our study we experienced relatively few adverse
drug reactions (ADR) associated with levofloxacin
(Table 5) (5) . Of 243 patients
taking levofloxacin, there were six reported cases of nausea,
four reports of diarrhea, and two reports of taste perversion.
In addition, five women reported mild or moderate vaginitis.
Adverse events for cefuroxime axetil were comparable. Similar
ADR have been noted for other quinolones but because levofloxacin
is given at a lower dosage, we would expect even fewer ADR.
I think levofloxacin is better tolerated than macrolides, as
gastrointestinal discomfort was comparatively less than typically
seen with macrolide therapy.

Q14. Could you
comment on the once-daily dosage schedule of levofloxacin you
used, and benefits this provides?

A14. Results from our study indicate that levofloxacin
is highly effective in the treatment of ABECB with a shorter
treatment period than cefuroxime axetil. We found that a significant
clinical response occurred in patients who took levofloxacin
once-daily for an average of seven days, compared to twice-daily
cefuroxime axetil for ten days. The ease of use of levofloxacin
combined with comparable clinical results may enhance patient
compliance beyond those observed with traditional empiric antibiotic
therapies. The use of levofloxacin offers a shorter course of
therapy, which means a less expensive prescription. This cheaper
form of therapy would is likely to further increase compliance,
which we would expect to be above average anyway when levofloxacin's
other advantages are considered.

Q15. Is resistance
to treatment a problem in this setting, and how does it impact
on your choice of treatment?

A15. Traditional antibiotics such as penicillin,
ampicillin, and amoxicillin are exhibiting diminishing clinical
and microbiologic activity against many of the most common respiratory
pathogens associated with ABECB. The growing incidence of ß-lactam
and macrolide resistance in these pathogens further complicates
the selection of an effective form of therapy. Most physicians
treat ABECB empirically and must consider several factors before
choosing a treatment. These include an antibiotics spectrum
of activity, the pathogens most likely to cause the infection,
the local pattern of bacterial resistance and the overall empiric
effectiveness of the antibiotic against pathogens associated
with ABECB. The fact that most bacteria are susceptible to levofloxacin
in addition to its ease of use make it a favorable form of therapy.

Q16. Is ß-lactamase
production by pathogens becoming a major problem, and could
you comment specifically on the development of multidrug-resistant
pneumococcus, and how this affects treatment?

A16. ß-lactamase production by pathogens has
been a problem for some time now and is becoming worse. We can
only assume that the development of multidrug resistant pneumococcus
will become much greater in the future, which will further limit
our ability to effectively treat ABECB. To combat this resistance,
combination therapies, higher doses of traditional therapies,
or alternative therapies must be utilised.

Q17. It has been
shown that in vitro MIC values do not always correspond
to actual in vivo activity. Could you comment on this
with reference to levofloxacin?

A17. I think it is possible that levofloxacin exhibits
greater in vivo activity against certain pathogens because
it is found in such high levels in the serum and it is distributed
so widely in the tissues. The fact that some in vitro
MIC values do not reflect in vivo activity could be attributed
to the dosing schedule. When susceptibility is noted in vivo
but not in vitro, it could be that higher doses may
have been used to treat the infection than those used when MIC
values were noted; thus, we would observe the pathogen overcoming
resistance.

Q18. From the
results of your clinical trial, and practical experience using
this drug, could you comment on other RTI you would recommend
levofloxacin be used for?

A18. We have seen outstanding results when using
levofloxacin to treat ABECB. I would use it for any RTI due
to similar pathogens, such as sinusitis, pharyngitis, and pneumonia,
including atypical or community-acquired pneumonia.

Q19. What are
the areas of future research that you think need to be carried
out regarding the use of fluoroquinolones, in particular levofloxacin,
in different RTI?

A19. Because levofloxacin has been proven so useful
in the treatment of ABECB it would be very beneficial to conduct
similar trials for sinusitis, pharyngitis and pneumonia. I would
like to see how well a higher dose of levofloxacin (or any fluoroquinolone)
could be tolerated. I would also welcome a study which paired
levofloxacin with other antibiotics, to show which combinations
work best.